A complex interaction between host genetics, commensal and pathogenic microflora, inorganic and organic environmental stresses (e.g., chemical toxins, pharmaceuticals, diet) combine to direct the onset as well as progression of chronic inflammatory diseases. Our understanding of inflammatory bowel disease has benefited greatly from the advent of genome-wide association studies (GWAS). In addition to confirming the role of established pathways such as pathogen sensors, innate signaling adapters, and cytokines/receptors, GWAS has identified significant associations between defects in cellular homeostatic processes such as autophagy or the ER stress response and increased risk of disease [1]. Indeed, defects in autophagy have been implicated in numerous inflammatory pathologies including lupus, rheumatoid arthritis, and neurodegeneration [2,3,4].

Autophagy directs the breakdown of intra-cellular cargo via lysosomal degradation and represents one of the two major pathways regulating protein homeostasis, the other being the ubiquitin-proteasome system. A Thr-300-Ala (T300A, rs2241880) missense variant in the key autophagy adapter gene Atg16l1 was identified as a consistent risk allele for Crohn’s disease by Hampe et al. [5], and numerous studies following this observation generated consistent findings with Atg16l1 gene deletion or hypomorph alleles in murine models [6, 7]. The molecular consequence of the T300A variant was revealed by two independent studies identifying that this amino acid change resulted in enhanced Caspase-mediated degradation of human and murine ATG16L1 [8, 9]. While phenotypes of enhanced inflammation upon deletion of core autophagy genes continue to be described, molecular mechanisms underlying these observations have remained unresolved. In addition, how inflammatory signaling is terminated when the initial stimulus is dissipated has yet to be fully elucidated. Does defective autophagy confer a generalized “pro-inflammatory” fate upon the cell and organism, or are particular inflammatory signaling nodes more susceptible to regulation by autophagy? Is this effect evoked by accumulating pro-inflammatory proteins that may be regulated by autophagy, leading to uncoordinated inflammatory responses? We posed this question in the context of Toll-like receptor (TLR) signaling [10], as this pathway is central to innate host defense and has been extensively characterized in the context of its major adapters TRIF and MYD88 [11]. Whereas MYD88 functions downstream of the majority of TLRs, TRIF (encoded by the gene Ticam1) lies downstream of TLR3 and 4 and can potentiate cell death as well as an inflammatory cytokine response [12].

Log in or create a free account to read this content

Gain free access to this article, as well as selected content from this journal and more on nature.com

Access through your institution

or

Sign in or create an account
Continue with Google
Continue with ORCiD